1. Field of the Invention
The present invention relates to an antitumor agent comprising, as an active ingredient, a liposome containing a shRNA molecule targeting a thymidylate synthase and the use thereof. In particular, the present invention relates to the use of such antitumor agent in combination with a chemotherapeutic agent.
2. Background Art
In recent years, RNAi molecules that cause RNA interference (hereafter referred to as “RNAi”) have been gaining attention as useful tools for treatment of tumors and the like. A variety of RNAi molecules that can inhibit tumor growth have been developed. The present inventors previously reported an RNAi molecule targeting thymidylate synthase (hereafter referred to as “TS”) involved in DNA synthesis. In addition, the present inventors reported that the RNAi molecule remarkably inhibits TS expression and thus exhibits the antitumor effects, and that the RNAi molecule potentiates the antitumor effects of a 5-FU antitumor agent (and particularly a compound drug of tegafur, gimeracil, and oteracil potassium) (WO2010/113844).
However, in general, RNAi molecules quickly disintegrate upon in vivo administration. Therefore, it has been very difficult to deliver RNAi molecules at sufficient amounts for targeting tumors.
In order to solve the above problems, a variety of RNAi molecule delivery methods are currently under development. For example, there is a method comprising incorporating DNA encoding an RNAi molecule (and particularly an RNAi molecule having a short hairpin structure (shRNA)) into an adequate vector and administering the vector (WO2010/113844). However, according to this method, it is necessary to directly inject the vector into a tumor for administration. In view of clinical application, an easier administration method (e.g., intravenous administration) has been awaited. In addition, methods for delivering RNAi molecules to tumor cells using complexes (lipoplexes) prepared by mixing an RNAi molecule with a liposome have been developed (Qixin Leng et al., Drug Future, 2009 September, 34(9), 721; Sherry Y. Wu et al., The AAPS Journal, Vol. 11, No. 4, December 2009; and B. Ozpolat et al., Journal of Internal Medicine 267; 44-53 2009). However, upon repetitive administration of such lipoplexes, the lipoplexes are quickly trapped by the cells of immune systems of living bodies to which the lipoplexes have been administered. In such case, sufficient RNAi effects cannot be obtained. In addition, such administration can cause serious side effects, which is problematic.
Therefore, a method for efficiently delivering RNAi molecules to tumors via in vivo administration still has been awaited in the art.